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5-HT2A/2C receptor signaling via phospholipase A2 and arachidonic acid is attenuated in mice lacking the serotonin reuptake transporter

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Abstract

Subjects

The serotonin reuptake transporter (SERT) helps to regulate brain serotonergic transmission and is the target of some antidepressants. To further understand SERT function, we measured a marker of regional brain phospholipase A2 (PLA2) activation in SERT knockout mice (SERT−/−) and their littermate controls (SERT+/+).

Methods

Following administration of 1.5 mg/kg s.c. (±)-2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI), a 5-HT2A/2C receptor agonist, to unanesthetized mice injected intravenously with radiolabeled arachidonic acid (AA), PLA2 activation, represented as the regional incorporation coefficient k* of AA, was determined with quantitative autoradiography in each of 71 brain regions.

Results

In SERT+/+ mice, DOI significantly increased k* in 27 regions known to have 5-HT2A/2C receptors, including the frontal, motor, somatosensory, pyriform and cingulate cortex, white matter, nucleus accumbens, caudate putamen, septum, CA1 of hippocampus, thalamus, and hypothalamus. In contrast, DOI did not increase k* significantly in any brain region of SERT−/− mice. Head twitches following DOI, which also were measured, were robust in SERT+/+ mice but were markedly attenuated in SERT−/− mice.

Conclusions

These results show that a lifelong elevation of the synaptic 5-HT concentration in SERT−/− mice leads to downregulation of 5-HT2A/2C receptor-mediated PLA2 signaling via AA and of head twitches, in response to DOI.

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Abbreviations

AA:

arachidonic acid

DOI:

(±)-2,5-dimethoxy-4-iodophenyl-2-aminopropane

5-HT:

5-hydroxytryptamine, serotonin

PLA2:

phospholipase A2

SERT:

serotonin reuptake transporter

SSRI:

selective serotonin reuptake inhibitor

sn:

stereospecifically numbered

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Acknowledgements

This work was supported in part by the National Alliance for Research on Schizophrenia and Depression (NARSAD) under a Distinguished Investigator Award to S.I. Rapoport.

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Authors and Affiliations

  1. Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Building 9, Room 1S128, Bethesda, MD, 20892, USA

    Ying Qu, Nelly Villacreses & Stanley I. Rapoport

  2. Laboratory of Clinic Science, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 20892, USA

    Dennis L. Murphy

  3. Neuroscience, Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA, 92130, USA

    Ying Qu

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  1. Ying Qu
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  2. Nelly Villacreses
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Correspondence to Ying Qu.

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Qu, Y., Villacreses, N., Murphy, D.L. et al. 5-HT2A/2C receptor signaling via phospholipase A2 and arachidonic acid is attenuated in mice lacking the serotonin reuptake transporter. Psychopharmacology 180, 12–20 (2005). https://doi.org/10.1007/s00213-005-2231-5

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